Exercise training in heart failure: reduction in angiotensin II, sympathetic nerve activity, and baroreflex control

Abstract

INVITED EDITORIALSExercise training in heart failure: reduction in angiotensin II, sympathetic nerve activity, and baroreflex controlCarlos E. Negrão, and Holly R. MiddlekauffCarlos E. Negrão, and Holly R. MiddlekauffPublished Online:01 Mar 2008https://doi.org/10.1152/japplphysiol.01368.2007This is the final version - click for previous versionMoreSectionsPDF (39 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat neurohumoral excitation has been considered the hallmark of heart failure. At the humoral level, cardiac dysfunction has been shown to be associated with increased angiotensin II, aldosterone, and vasopressin levels. The clinical implication for such humoral dysregulation is the increase in salt and water retention, which contributes to clinical heart failure. It has also been shown that patients with cardiac dysfunction have augmented peripheral norepinephrine levels and cardiac norepinephrine spillover. In addition, elevations in muscle sympathetic nerve activity levels directly measured in the peroneal nerve by microneurography correlate with the severity of heart failure.Accumulating evidence shows that sympathetic hyperactivity plays an important role in the vasoconstrictor state of heart failure. Patients with chronic heart failure have greater renal cortical vascular resistance and muscle vascular resistance than healthy individuals (5). Phentolamine, an α1-adrenoceptor antagonist, infused into the brachial artery significantly increases forearm blood flow in patients with severe cardiac dysfunction. Moreover, in contrast to acetylcholine alone, acetylcholine associated with phentolamine increases forearm vascular conductance responses during mental stress toward normal levels (9). Unknown are the causes of sympathoexcitation in heart failure. Alterations in arterial and cardiopulmonary baroreceptors, central and peripheral chemoreceptors, cardiac chemoreceptors, and central nervous system abnormalities have all been proposed to contribute to the increased sympathetic activity in heart failure.Persistent morbidity and mortality in patients with heart failure, despite advances in pharmacological treatment, have led many investigators to search for new strategies in the treatment of heart failure. Exercise training has emerged as a new and efficient nonpharmacological treatment for patients with heart failure. Dr. Zucker's group has provided many contributions to our understanding of the mechanisms underlying the beneficial effects of exercise in heart failure. Using a pacing-induced model of heart failure in rabbits, these investigators (4) have previously reported that exercise training for 1 mo significantly reduced renal sympathetic nerve activity. These findings were recently confirmed in a rat model of ischemia-induced heart failure (7). Similar findings have been reported in humans. Four months of exercise training significantly reduced muscle sympathetic nerve activity levels in patients with chronic heart failure and ejection fraction <45% and categorized as functional class II and III under New York Heart Association guidelines (8). This decrease in muscle sympathetic nerve activity was so dramatic that muscle sympathetic nerve activity levels after exercise training were not different from those observed in healthy controls.The mechanisms underlying the powerful effect of exercise training on sympathetic hyperactivity in heart failure remain under investigation. Liu et al. (4) have reported that exercise training restored arterial baroreflex control of renal sympathetic nerve activity and heart rate, which was associated with an improvement in the aortic depressor sensitivity (7). At the central nervous system level, exercise training reduces angiotensin II type I receptors in the paraventricular nucleus, rostral ventrolateral medulla, and nucleus tract solitarius (11). In a recent study, Gao et al. (1) demonstrated that the normalization in renal sympathetic nerve activity and arterial baroreflex control in rabbits with pacing-induced heart failure was associated with an upregulation of superoxide dismutase and a downregulation of the NADPH oxidase subunit gp91 expression in the rostral ventrolateral medulla.In the recent article in the Journal of Applied Physiology by Mousa et al. (6), the group demonstrates that exercise training reduces renal sympathetic nerve activity and improves arterial baroreflex sensitivity in rabbits with pacing-induced heart failure. In addition, these investigators show that exercise training prevents the increase in angiotensin II and downregulated mRNA and protein expression of angiotensin type I receptors in the rostral ventrolateral medulla in this animal model of heart failure. Interestingly, when angiotensin II levels were maintained experimentally near levels of untrained rabbits with heart failure, the amelioration in arterial baroreflex sensitivity was prevented. These findings are consistent with the notion that the improvement in the arterial baroreflex control and central nervous system integration depends on the reduction in angiotensin II and angiotensin type I receptors in the rostral ventrolateral medulla.As with all good scientific studies, the Mousa et al. (6) study leaves us with more questions than it answers. 1) How does exercise training decrease angiotensin II levels? 2) Is there a threshold effect for the amount and type of exercise necessary to decrease angiotensin II levels, or is it a continuum? Wisløff et al. (10) have recently reported that patients with postinfarction heart failure submitted to aerobic interval training had a more effective reversion of the left ventricular remodeling and improved aerobic capacity, endothelial function, and quality of life than when submitted to moderate continuous exercise training. 3) Is there a threshold effect at which circulating angiotensin II will trigger increases in sympathetic nerve activity, or is this a graded effect? 4) Finally, is exercise training an acceptable alternative to pharmacological interruption of the renin-angiotensin-aldosterone system, especially in patients in whom low blood pressure or intolerable side effects prohibit adequate pharmacological dosing?What are the implications of the inhibitory sympathetic changes caused by exercise training in heart failure? The obvious consequence of the sympathetic inhibition is the increase in peripheral blood flow and oxygen supply. These responses reduce the expression of inflammatory cytokines and the production of reactive oxygen species. These antioxidative effects of exercise training are further demonstrated by the normalization of lipid peroxidation and nitrotyrosine formation in skeletal muscle of patients with heart failure (3). Moreover, the anti-inflammatory effect of exercise training restores oxidative capacity in heart failure, since there is an inverse correlation between the decrease in inducible nitric oxide synthase and the mitochondrial isoform of creatine kinase (2). Finally, the reduction in inflammatory cytokines may decrease protein degradation via the ubiquitin/proteasome system and muscle atrophy. All of these changes associated with exercise training seem to act in concert to increase exercise tolerance and quality of life in patients with heart failure.GRANTSC. E. Negrao was supported by Conselho National de Densenvolvimento Científico e Tecnológico Grant 304304/2004-2, Brazil, and H. R. Middlekauff by National Institutes of Health Grant RO1 HL-084525.REFERENCES1 Gao L, Wang W, Liu D, Zucker IH. Exercise training normalizes sympathetic outflow by central antioxidant mechanisms in rabbits with pacing-induced chronic heart failure. Circulation 115: 3095–3102, 2007.Crossref | PubMed | ISI | Google Scholar2 Hambrecht R, Adams V, Gielen S, Linke A, Möbius-Winkler S, Yu J, Niebauer J, Jiang H, Fiehn E, Schuler G. Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle. J Am Coll Cardiol 33: 174–179, 1999.Crossref | PubMed | ISI | Google Scholar3 Linke A, Adams V, Schulze PC, Erbs S, Gielen S, Fiehn E, Möbius-Winkler S, Schubert A, Schuler G, Hambrecht R. Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle. Circulation 111: 1763–1770, 2005.Crossref | PubMed | ISI | Google Scholar4 Liu JL, Irvine S, Reid IA, Patel KP, Zucker IH. Chronic exercise reduces sympathetic nerve activity in rabbits with pacing-induced heart failure: a role for angiotensin II. Circulation 102: 1854–1862, 2000.Crossref | PubMed | ISI | Google Scholar5 Middlekauff HR, Nguyen AH, Negrão CE, Nitzsche EU, Hoh CK, Natterson BA, Hamilton MA, Fonarow GC, Hage A, Moriguchi JD. Impact of acute mental stress on sympathetic nerve activity and regional blood flow in advanced heart failure. Circulation 96: 1835–1842, 1997.Crossref | PubMed | ISI | Google Scholar6 Mousa TM, Liu D, Cornish KG, Zucker IH. Exercise training enhances baroreflex sensitivity by an angiotensin II-dependent mechanism in chronic heart failure. J Appl Physiol (December 13, 2008). doi:10.1152/japplphysiol.00601.2007.Link | ISI | Google Scholar7 Rondon E, Brasileiro-Santos MS, Moreira ED, Rondon MU, Mattos KC, Coelho MA, Silva GJ, Brum PC, Fiorino P, Irigoyen MC, Krieger EM, Middlekauff HR, Negrão CE. Exercise training improves aortic depressor nerve sensitivity in rats with ischemia-induced heart failure. Am J Physiol Heart Circ Physiol 91: H2801–H2806, 2006.Google Scholar8 Roveda F, Middlekauff HR, Rondon MU, Reis SF, Souza M, Nastari L, Barreto AC, Krieger EM, Negrão CE. The effects of exercise training on sympathetic neural activation in advanced heart failure: a randomized controlled trial. J Am Coll Cardiol 42: 854–860, 2003.Crossref | PubMed | ISI | Google Scholar9 Santos AC, Alves MJ, Rondon MU, Barreto AC, Middlekauff HR, Negrão CE. Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients. Am J Physiol Heart Circ Physiol 289: H593–H599, 2005.Link | ISI | Google Scholar10 Wisløff U, Støylen A, Loennechen JP, Bruvold M, Rognmo Ø, Haram PM, Tjønna AE, Helgerud J, Slørdahl SA, Lee SJ, Videm V, Bye A, Smith GL, Najjar SM, Ellingsen Ø, Skjaerpe T. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation 115: 3086–3094, 2007.Crossref | PubMed | ISI | Google Scholar11 Zucker IH, Patel KP, Schultz HD, Li YF, Wang W, Pliquett RU. Exercise training and sympathetic regulation in experimental heart failure. Exerc Sport Sci Rev 32: 107–111, 2004.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: C. E. Negrão, Instituto do Coração (InCor), Unidade de Reabilitação Cardiovascular e Fisiologia do Exercício, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, SP CEP 05403-000, Brazil (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByAssociation of physical activity levels and the prevalence of COVID-19-associated hospitalizationJournal of Science and Medicine in Sport, Vol. 24, No. 9Central losartan administration increases cardiac workload during aerobic exerciseNeuropeptides, Vol. 77The role of nervous system in adaptive response of bone to mechanical loading9 November 2018 | Journal of Cellular Physiology, Vol. 234, No. 6Angiotensin converting enzyme 2 polymorphisms and postexercise hypotension in hypertensive medicated individuals7 December 2016 | Clinical Physiology and Functional Imaging, Vol. 38, No. 2Impact of exercise training associated to pyridostigmine treatment on autonomic function and inflammatory profile after myocardial infarction in ratsInternational Journal of Cardiology, Vol. 227Revisiting the Debate: Does Exercise Build Strong Bones in the Mature and Senescent Skeleton?13 September 2016 | Frontiers in Physiology, Vol. 7Exercise training attenuates the pressor response evoked by peripheral chemoreflex in rats with heart failureCanadian Journal of Physiology and Pharmacology, Vol. 94, No. 9Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise7 April 2016 | Hypertension Research, Vol. 39, No. 7Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptorCarolin Pügge, Jai Mediratta, Noah J. Marcus, Harold D. Schultz, Alicia M. Schiller, and Irving H. Zucker1 February 2016 | Journal of Applied Physiology, Vol. 120, No. 3Exercise training attenuates chemoreflex-mediated reductions of renal blood flow in heart failureNoah J. Marcus, Carolin Pügge, Jai Mediratta, Alicia M. Schiller, Rodrigo Del Rio, Irving H. Zucker, and Harold D. Schultz15 July 2015 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 309, No. 2Modulation of angiotensin II signaling following exercise training in heart failureIrving H. Zucker, Harold D. Schultz, Kaushik P. Patel, and Hanjun Wang15 April 2015 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 308, No. 8Central mechanisms for exercise training-induced reduction in sympatho-excitation in chronic heart failureAutonomic Neuroscience, Vol. 188ACE2/Ang-(1-7)/Mas Axis and Physical ExerciseExercise Training Reduces Cardiac Dysfunction and Remodeling in Ovariectomized Rats Submitted to Myocardial Infarction31 December 2014 | PLoS ONE, Vol. 9, No. 12Intercostal and forearm muscle deoxygenation during respiratory fatigue in patients with heart failure: potential role of a respiratory muscle metaboreflex29 August 2014 | Brazilian Journal of Medical and Biological Research, Vol. 47, No. 11Exercise perspective on common cardiac medicationsIntegrative Medicine Research, Vol. 2, No. 2Exercise training prevents skeletal muscle afferent sensitization in rats with chronic heart failureHan-Jun Wang, Yu-Long Li, Irving H. Zucker, and Wei Wang1 June 2012 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 302, No. 11Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle functionBrazilian Journal of Medical and Biological Research, Vol. 44, No. 9Exercise training prevents the exaggerated exercise pressor reflex in rats with chronic heart failureHan-Jun Wang, Yan-Xia Pan, Wei-Zhong Wang, Lie Gao, Matthew C. Zimmerman, Irving H. Zucker, and Wei Wang1 May 2010 | Journal of Applied Physiology, Vol. 108, No. 5Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failureIrving H. Zucker, Harold D. Schultz, Kaushik P. Patel, Wei Wang, and Lie Gao1 November 2009 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 297, No. 5 More from this issue > Volume 104Issue 3March 2008Pages 577-578 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01368.2007PubMed18174387History Published online 1 March 2008 Published in print 1 March 2008 Metrics